Understanding and Targeting Tumor Microenvironment in Prostate Cancer to Inhibit Tumor Progression and Castration Resistance
Technical Report,30 Sep 2015,29 Sep 2016
MD Anderson Cancer Center Houston United States
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The signaling mechanisms between prostate cancer cells and infiltrating immune cells may illuminate novel therapeutic approaches. In Year2, utilizing a prostate adenocarcinoma model driven by loss of Pten and Smad4, I further validated that polymorphonuclear myeloid-derived suppressor cells MDSCs are the major infiltrating immune cell type and depletion of MDSCs blocks progression. Employing a novel dual reporter prostate cancer model, epithelial and stromal transcriptomic profiling identified Cxcl5 as a cancer-secreted chemokine to attractCxcr2-expressing MDSCs and, correspondingly, pharmacological inhibition of Cxcr2 impeded tumor progression. Integrated analyses identified hyperactivated Hippo-YAP signaling in driving Cxcl5 upregulation in cancer cells through YAP-TEAD complex and promoting MDSCs recruitment. Clinico-pathological studies reveal upregulation and activation of YAP1 in a subset of human prostate tumors, and theYAP1 signature is enriched in primary prostate tumor samples with stronger expression of MDSC relevant genes. Together, YAP-driven MDSC recruitment via heterotypic Cxcl5-Cxcr2 signaling reveals effective therapeutic strategy for advanced prostate cancer.
- Medicine and Medical Research